The invention is generally in the field of methods of inhibiting angiogenesis, and more specifically is drawn to methods and compositions for inhibiting angiogenesis.
Current treatments of cancer and related diseases have limited effectiveness and numerous serious unintended effects. Based primarily on chemical, radiation and surgical therapy, these treatments have progressed only incrementally during more than thirty years of intensive research to discover the origins and devise improved therapies of neoplastic diseases.
Current research strategies emphasize the search for effective therapeutic modes with less risk, including the use of natural products and biological agents. This change in emphasis has been stimulated by the fact that many of the consequences, to patients and their offspring, of conventional cancer treatment, including new cancers, mutations and congenital defects, result from their actions on genetic material and mechanisms. Hong et al., J. Natl. Cancer Inst. Monogr. 17:49-53 (1995). Efforts continue to discover the origins of cancer at the genetic level, and correspondingly new treatments, but such interventions also may have serious unanticipated effects.
The observation by Folkman that tumors are highly vascular, and the elucidation by him and others of a process termed angiogenesis through which many tumors derive a blood supply by the generation of microvessels, provided an important new avenue to therapy of cancer and other diseases and disorders. Folkman, Proc. Natl. Acad. Sci. U.S.A. 95(16):9064-6 (1998); C. R. Acad. Sci. III 316(9):909-918 (1993). Angiogenesis has now been recognized in inflammatory lesions and benign tumors, in addition to malignant tumors.
Mammals are characterized by complex cardiovascular systems that enable their warm-blooded nature, internal embryonic and fetal development and successful population of extreme habitats. The development of an extensive capillary system, specialized in each organ and tissue, is an essential feature of mammalian cardiovascular systems, to provide optimal distribution of nutrients and other substances including hormones and defensive agents. The metabolic and physiologic needs of mammalian cells are met by their proximity to capillaries, and limited resources may be diverted by imbalance of this supply system. Tortora, xe2x80x9cPrinciples of Human Anatomyxe2x80x9d, 5th ed., pp. 371-372, Harper and Row, N.Y. (1989).
Angiogenesis results primarily from the development of new or lengthened capillaries, and larger microvessels. Capillaries are formed primarily of specialized endothelial cells and the connective tissue layer to which they adhere, the basement membrane. The proliferation of endothelial cells and their migration and orientation to form capillaries is recognized as the key process regulated in the control of angiogenesis. Neovascularization is a form of angiogenesis marked by formation of blood vessels in a tissue or region previously devoid of blood vessel supply, for example the cornea of the eye. The mechanisms involved in angiogenesis are quite complicated, however, and no one appears to be the sole controlling mechanism.
Mammals have effective mechanisms to regulate this vital process. Stimulation of angiogenesis in adult mammals, other than as a part of normal tissue repair, pregnancy or the menstrual cycle, is abnormal and often pathological. Many malignant tumors, benign tumors and inflammatory lesions have the ability to evade or mobilize these regulatory mechanisms to support their growth and further malignant progression.
Development of effective preventive and treatment means has been hampered by inadequate understanding of the factors controlling this process. The premise of therapeutic development for such conditions is that effective treatment does not require destruction of the cells or tissues of origin. Reduction or prevention of the increased blood supply can be sufficient to prevent their growth, and the manifestation of the condition as a disease or pathological disorder.
This concept was initially rejected, but widespread recognition of angiogenesis as a major factor in a variety of pathological conditions and diseases, particularly cancer and pre-cancerous conditions, has occurred recently among scientists and businesses. It is estimated that 184 million U.S. and European Union (EU) disease cases could benefit from treatment to inhibit angiogenesis that is inappropriate and pathological (anti-angiogenic therapy), in addition to an estimated 314 million disease cases in the U.S. and EU that might benefit from treatment to stimulate angiogenesis, for example in cardiac rehabilitation. Thirty-one specific projects of pharmaceutical and biotechnology companies to develop anti-angiogenic treatment were reported in Gen. Eng. News 18(17):1, 8, 34, 46 (1998).
It is an object of the present invention to provide methods of treating a mammal having a disease or condition characterized by increased angiogenesis.
It is a further object of the present invention to provide a method of preventing the initiation or progression of a disease or condition characterized by increased angiogenesis in a mammal, especially skin diseases and diseases characterized by elevated basic fibroblast growth factor.
Methods for treating diseases or disorders of the skin which are characterized by angiogenesis have been developed using curcumin and curcumin analogs. Based on the results obtained with curcumin, it has been determined that other angiogenesis inhibitors can also be used to treat these skin disorders. It was also discovered that curcumin acts to inhibit angiogenesis in part by inhibition of basic fibroblast growth factor (bFGF), and thereby provides a means for treating other disorders characterized by elevated levels of bFGF, such as bladder cancer, using curcumin and other analogues which also inhibit bFGF.
Curcumin and demethoxycurcumin are the preferred agents for treating these disorders. The preferred means of administration is to apply the curcumin topically, for example, as an ointment or hydrogel containing between one-half percent (0.5%) and five percent (5%) of the curcumin, or regionally, orally to treat disorders of the gastrointestinal tract or by instillation, to treat bladder or cervical cancer. In alternative embodiments, the curcumin or its analogs can be implanted in the form of one or more pellets of a pharmaceutically acceptable vehicle encapsulating or encorporating the curcumin, or by one or more injections of a pharmaceutically acceptable aqueous solution including the curcumin.
Representative skin disorders include the malignant diseases angiosarcoma, hemangioendothelioma, basal cell carcinoma, squamous cell carcinoma, malignant melanoma and Karposi""s sarcoma, and the non-malignant diseases or conditions including psoriasis, lymphangiogenesis, hemangioma of childhood, Sturge-Weber syndrome, verruca vulgaris, neurofibromatosis, tuberous sclerosis, pyogenic granulomas, recessive dystrophic epidermolysis bullosa, venous ulcers, acne, rosacea, eczema, molluscum contagious, seborrheic keratosis, and actinic keratosis. Representative disorders characterized by increased levels of bFGF include bladdar and cervical cancers.
As demonstrated in the examples, curcumin and its analogs are potent inhibitors of endothelial cell proliferation, a sensitive test of in vitro antiangiogenic effectiveness, and also of corneal neovascularization, a sensitive and reliable test of in vivo antiangiogenic effectiveness. The examples demonstrate that this inhibition is exerted directly on the endothelial cells that are primarily involved in angiogenesis, and not indirectly through other effects of these agents. The examples further demonstrate that curcumin and its analogs inhibit the stimulation of angiogenesis in vivo by basic fibroblast growth factor.